Introduction: Rheumatoid arthritis (RA) clinical guidelines do not provide strong recommendations for the choice of disease-modifying anti-rheumatic drugs (DMARD) in patients with an inadequate response to methotrexate (MTX), and only limited evidence is available on factors influencing rheumatologist treatment decisions. We aimed to describe therapeutic preferences after the failure of a first-line strategy of MTX in simulated cases of patients with RA. Methods: Fictional but realistic case-vignettes (n = 64) of patients with RA and an inadequate response to MTX were developed with a combination of RA-poor prognostic factors and comorbidities. Physicians were presented with eight vignettes and chose the most and least appropriate therapeutic option from the following six options randomly proposed 3 by 3: (1) replacing MTX with another csDMARD; (2) combining MTX with one or more csDMARDs; (3) adding a bDMARD of either TNF inhibitors (TNFi), tocilizumab (TCZ), abatacept (ABA), or rituximab (RTZ). A total of 1605 complete case vignettes were produced and randomly assigned to a representative sample of French rheumatologists. For each vignette, whenever a treatment was preferred, one point was incremented for this treatment; if this treatment was the least desired, one point was removed. Preferences were elicited using a normalized best–worst score. Results: Two hundred and four French rheumatologists participated in the study with each vignette being assessed 20–28 times for a completion rate of 94%. TNFi was the first-choice strategy (80% of vignettes), except in cases with a history of infection and pulmonary comorbidity, where ABA was the first preference (85%). TCZ came third in 83% of the cases. Other options were never preferred and repeatedly yielded negative scores. Conclusions: We observed a conservative trend with TNFi as the main therapeutic choice for patients with RA and inadequate response to MTX. Preference for bDMARD-based strategies increased with the number of RA-poor prognosis factors, whereas an increase in the number of comorbidities resulted in an increased preference for ABA. Understanding clinical decision-making will be particularly important as the therapeutic landscape for RA continues to evolve.